Chronic kidney disease (CKD) represents a major and costly comorbidity in type 2 diabetes management. Identifying individuals with high healthcare costs due to CKD will support decision-making for early intervention. We used latent class analysis (LCA) to classify Chinese individuals with type 2 diabetes and incident CKD based on their demographic and clinical profiles. For this study, 2886 individuals with type 2 diabetes and incident CKD and complete data for 42 attributes were selected from the prospective Hong Kong Diabetes Register cohort (2007-2019). We used LCA to select 14 variables to classify participants, followed by a hierarchical generalised linear mixed model to evaluate longitudinal healthcare costs among class memberships. During 109,784 person-years of follow-up, the incidence of CKD was 26.29 per 1000 person-years with a per-patient-per-year (PPPY) cost of US$4395±11,947 (mean±standard deviation). The four distinct classes used in the LCA based on baseline profiles were as follows: Class 1 (18.3%; PPPY: US$6087±15,519), namely those who were young at onset (44.4±10.3 years), had moderate comorbidities (25.6% had a moderate or high score on the Elixhauser Comorbidity Index [ECI]) and used multiple medications (90.2% used at least three medications); Class 2 (21.2%; PPPY: US$3822±9816), namely those who had old-age onset (66.9±6.9 years), had moderate comorbidities (27.8% had a moderate or high ECI score) and used multiple medications (70.7% used at least three medications); Class 3 (33.9%; PPPY: US$4260±11,725), namely those who were middle-aged at onset (54.2±10.0 years), had few comorbidities (14.0% had a moderate or high ECI score) and used few medications (15.6% used at least three medications); and Class 4 (26.5%; PPPY: US$3923±10,957), namely those who were middle-aged at onset (54.1±7.6 years), had moderate comorbidities (25.3% had a moderate or high ECI score) and used multiple medications (98.9% used at least three medications). Class 1 (young onset) and Class 3 (middle-aged onset) incurred the highest cost during the year of CKD onset, with those in Class 1 having more comorbidities than those in Class 3 at baseline. Multiple healthcare services contributed to the high healthcare costs in Class 1, with costs in Class 3 attributed mainly to post-CKD outpatient and psychiatric care. Those with young-onset type 2 diabetes incurred the highest cost during the year of CKD onset. Individuals with middle-aged onset type 2 diabetes with fewer comorbidities and less intensified treatment at baselinealso had subsequent increased healthcare costs.

BackgroundLate‐onset ulcerative colitis (UC) has become prevalent in recent years. The differences between late‐onset, middle aged–onset, and early‐onset UC have not been fully elucidated.MethodsThe clinical characteristics, steroid side effects, remission rates, and surgical rates of UC patients were retrospectively studied. Patients were allocated to three groups according to age at diagnosis: late‐onset group (≥ 65 years), middle aged–onset (50–64 years), and early‐onset group (≤ 49 years).ResultsClinical characteristics such as admission age, duration of disease, history of cancer, days to diagnosis, clinical activity on admission, hemoglobin level on admission, and steroid use were significantly different between the three groups. The side effects of steroids were significantly more common in the late‐onset group. The remission induction rates differed significantly between the three groups: 67.7%, 71.7%, and 83.6% in the late‐onset, middle aged–onset, and early‐onset groups. Surgery rates were significantly higher in the late‐onset group: Surgery rates in the late‐onset, middle aged–onset, and early‐onset groups were 14.2%, 3.4%, and 3.4% at 12 months of diagnosis, and 23.8%, 10.3%, and 4.2% at 24 months of diagnosis.ConclusionsIn conclusion, remission rates were low and surgical rates were higher with increasing age of onset. In addition, steroid‐related side effects increased with age. It was possible that late‐onset UC may have a different pathogenesis and be resistant to treatment.

ObjectivesTo explore the associations between arterial stiffness (AS) onset age and type 2 diabetes mellitus (T2DM) risk.DesignLarge-scale cohort study.SettingThe largest medical centre in central China.ParticipantsThis study enrolled 22 588 participants free of T2DM at baseline. All participants took an annual physical examination from 2012 to 2016, with fasting blood glucose and brachial–ankle pulse wave velocity measurements.Primary and secondary outcome measuresCox proportional model was used to investigate the association between AS onset age and T2DM risk. Sex-specific analysis was also performed, and the association between early vascular ageing (EVA), normal vascular ageing (NVA), supernormal vascular ageing (SUPERNOVA) onset age and diabetes risk was also examined.ResultsA total of 757 (3.4%) participants were diagnosed with T2DM. Compared with participants free of AS in each specific age group, the earlier AS onset age was more strongly associated with T2DM risk, especially for middle age, with the fully adjusted hazard risk (HR) and 95% CI of 4.63 (2.79–7.67) for AS onset age at 50. Similar results were observed both in males and females, with the fully adjusted HR and 95% CI of 4.54 (2.60 to 7.93) for males and 4.86 (1.48 to 16.01) for females, with AS onset age at 50. Such an association was also observed in the exploration of EVA, NVA and SUPERNOVA onset age and incident T2DM risk.ConclusionThis study revealed that the middle-aged onset of AS was more significantly associated with a higher T2DM risk. Early screening of AS, especially in middle age, may assist in T2DM detection and postpone diabetic vascular complications.

INTRODUCTIONThe impact of smoking behaviors on asthma incidence and all-cause mortality among middle-aged and older adults remains understudied. In particular, whether the potential effect of adolescent smoking initiation on late-onset asthma is independent of cumulative tobacco exposure is unclear.METHODSCox proportional hazards models assessed longitudinal impact of smoking behaviors on asthma incidence and mortality risks using 2011–2018 China Health and Retirement Longitudinal Study (CHARLS) data. Cross-sectional smoking-asthma associations were analyzed with logistic regression. Additionally, restricted cubic splines were used to assess the nonlinear relationships between smoking characteristics and asthma incidence.RESULTSSmokers had a 65% higher risk of incident asthma compared to non-smokers in middle-aged and older adults (HR=1.65; 95% CI: 1.10–2.46, p=0.015). According to stratified analysis, individuals with smoking duration ≥40 years (HR=1.95; 95% CI: 1.2–3.15, p=0.007), cumulative pack-years under 15 pack-years (HR=1.76; 95% CI: 1.04–2.99, p=0.035), and smoking onset before the age of 18 years (HR=2.31; 95% CI: 1.35–3.96, p=0.002) were at significantly greater risk for asthma. After controlling for cumulative pack-years, early smoking initiation (<18 years) remained an independent and significant predictor of asthma onset in middle and older age (HR=2.56; 95% CI: 1.29–5.06, p=0.007). Subgroup analysis revealed that smoking-related asthma risk was especially elevated among those aged <65 years, females, overweight individuals, and those without baseline comorbidities. Moreover, there was no significant difference in all-cause mortality between the smoking and non-smoking groups in asthma patients.CONCLUSIONSThe increased risk of asthma onset among middle-aged and older adults due to adolescent smoking initiation was independent of cumulative smoking pack-years, even though low pack-years and long-term smoking also contribute to increased risk. Targeted smoking cessation programs, especially adolescent prevention, are crucial to reduce asthma burden in this population.

ObjectivesTo investigate whether clinical outcomes and patient-reported outcomes (PROs) differ over 2 years based on the age of onset of RA.MethodsAll RA patients from the tREACH trial, a multicentre, stratified, single-blinded trial with a treat-to-target management approach and a fixed medication protocol were included. The age of disease onset was categorized into young-onset RA (YORA) (<45 years, n = 119), middle-aged onset RA (MORA) (45–65 years, n = 208) and elderly-onset RA (EORA) (>65 years, n = 98) at the time of diagnosis. Mixed models were used to compare clinical outcomes and PROs over time. The following PROs were included: pain (Numeric Rating Scale), fatigue (visual analogue scale), functional ability (HAQ-Disability Index, HAQ-DI), quality of life (European Quality of Life 5-Dimensions 3-Levels, EQ-5D-3L), and possible depression (Hospital Anxiety and Depression Scale-Depression, HADS-D) or anxiety disorder (HADS-Anxiety, HADS-A).ResultsAt diagnosis, EORA patients had more swollen joints, erosions and comorbidities than younger patients. However, disease activity remained similar across age groups at diagnosis and over time. After 2 years of follow-up, bDMARD usage was 30%, 30% and 15% in YORA, MORA and EORA patients, respectively. EORA patients also experienced less pain and fatigue over time compared with YORA patients [1 (95% CI 0.5–1.6) and 17.3 mm (11.3–23.4) lower] and MORA patients [0.6 (0.1–1) and 5.8 mm (0.7–10.9) lower]. No other clinically relevant PRO differences were observed.ConclusionDespite unfavourable prognostic factors at diagnosis, EORA patients have similar outcomes compared with their younger counterparts if a treat-to-target management approach is applied. Notably, fewer EORA patients required bDMARDs to reach the same treatment target.

Prior research has shown varying suicide attempt rates based on the age of onset in major depressive disorder (MDD) patients. However, there is a paucity of research on psychotic major depressive disorder (PMD) patients. This study aimed to assess the prevalence and correlates of suicide attempts in PMD patients stratified by age of onset. Totally, 1718 first-episode drug-naïve MDD outpatients were recruited, divided into early-age onset (EAO) and middle-age onset (MAO) based on the first episode before age 45/after age 45. Clinical severity was assessed using the Hamilton Depression Rating Scale (HAMD), the Hamilton Anxiety Rating Scale (HAMA) and the Positive and Negative Syndrome Scale (PANSS) positive subscale. In addition, thyroid hormone and glucolipid metabolism indicators were measured. In EAO PMD patients, HAMA scale score and thyroid-stimulating hormone (TSH) levels were associated with suicide attempts. The area under the receiver operating characteristic curve (AUROC) was 0.892. In MAO PMD patients, TSH and diastolic blood pressure were associated with suicide attempts. The AUROC was 0.862. This study demonstrates that the prevalence and correlates of suicide attempts vary among PMD patients with different ages of onset. Age of onset should be considered in the prevention and treatment of suicide attempts in patients with PMD.

To investigate the similarities and differences of clinical manifestations and long-term prognosis between eosinophilic gastroenteritis (EGE) and eosinophilic granulomatosis with polyangiitis (EGPA) complicating GI involvement (EGPA-GI). Sixty-two EGE and 30 EGPA-GI patients were retrospectively enrolled in PUMCH from 2008 to 2023. Baseline clinical records were collected. Kaplan-Meier curves and log-rank tests were used to analyzed the relapse-free and non-adverse-outcome survival rate. Logistic regression was used to construct a predictive model for diagnosing EGE and EGPA-GI. Both diseases had a middle age onset. EGE had a shorter disease duration (3.5 vs. 11.0 months, p = 0.023), higher prevalence of distension (50.0% vs 20.0%, p = 0.007) and intestinal obstruction (32.3% vs 3.3%, p = 0.001), and lower prevalence of fever (6.5% vs 50.0%, p < 0.001) than EGPA-GI. EGPA-GI had higher prevalence of allergic diseases (86.7% vs 46.8%, p < 0.001) and higher IgE level (445.0 KU/L vs 153.0 KU/L, p = 0.003). Meanwhile, in EGPA-GI, higher ESR (25.0 mm/h vs 4.0 mm/h, p = 0.001) and hsCRP (48.9 mg/L vs 1.8 mg/L, p < 0.001) were observed. Asthma (OR 572.043, 95% CI 21.729-176,210.429, p = 0.0043), fever (OR 25.221, 95% CI 2.334-585.159, p = 0.0157), rash (OR 28.671, 95% CI 1.898-2274.543, p = 0.454), intestinal obstruction (OR 0.015, 95% CI 0.000-0.357, p = 0.0318), higher ESR (OR 1.101, 95% CI 1.035-1.208, p = 0.0099), and hsCRP (OR 1.038, 95% CI 1.010-1.081, p = 0.0208) were found to be independent discriminating factors for EGPA-GI. Both diseases presented recurrent courses. Adverse outcomes including GI perforation, organ failure, and all-cause death occurred in seven EGPA-GI patients while none in EGE (p = 0.00011). Both diseases have chronic and recurrent disease courses. Clinical manifestations and laboratory tests help to discriminate them. EGPA-GI have more unfavorable prognosis compared with EGE during long-term follow-up. Key Points •Baseline characteristics and long-term prognosis of 62 EGE and 30 EGPA patients with GI involvement (EGPA-GI) were compared in this study. •Both diseases had chronic and recurrent disease duration, eosinophilia, and increased IgE level. •EGPA-GI had higher prevalence of asthma, fever, rash, higher IgE, ESR, and CRP compared with EGE. •EGPA-GI had higher risk for severe adverse outcomes.

To estimate the incidence and identify risk factors for diagnosed type 2 diabetes (T2D) among young U.S. adults. We analyzed 142,884 adults aged 18-79 years with self-reported diabetes type from the cross-sectional National Health Interview Survey in 2016-2022, representing the noninstitutionalized U.S. civilian population. Incidence of diagnosed T2D was calculated for three age groups: young-adult onset (18-44 years), middle-age onset (45-64 years), and older-adult onset (65-79 years); the latter two groups were included to highlight the distinct risk factor profile of young-adult-onset T2D. Multivariable logistic regressions were used to identify risk factors for young-adult-onset T2D. The estimated incidence of diagnosed young-adult-onset T2D was 3.0 per 1,000 adults (95% CI 2.6-3.5). Minority groups, socioeconomically disadvantaged individuals, and people with cardiometabolic diseases or psychological conditions had a higher incidence of diagnosed young-adult-onset T2D compared with their counterparts. Lipid-lowering medication use (adjusted odds ratio [aOR] 13.15, 95% CI 8.85-19.55), antihypertensive medication use (aOR 11.89, 95% CI 7.97-17.73), and obesity (BMI ≥30 vs. <25 kg/m2, aOR 10.89, 95% CI 6.69-17.7) were the strongest risk factors for young-adult-onset T2D; these risk factors, along with hypertension, hyperlipidemia, and coronary heart disease, were more strongly associated with young-adult-onset T2D compared with later-onset T2D, with up to 4.5 times higher aORs. This study quantified the incidence of diagnosed young-adult-onset T2D in U.S. adults and identified its distinct risk factor profile. Targeted prevention strategies for young-adult-onset T2D are needed for minority and socioeconomically disadvantaged people and those with cardiometabolic diseases.

Journal Article A hidden cause of middle-aged onset heart failure with preserved ejection fraction: a GTPBP3 variant Get access Toshiyuki Yano, Toshiyuki Yano Department of Cardiovascular, Renal and Metabolic Medicine, Sapporo Medical University School of Medicine, South-1, West-16, Chuo-ku, Sapporo 060-8543, Japan Corresponding author. Tel: +81 11 611 2111 ext. 3225, Fax: +81 11 644 7958, Email: tyano@sapmed.ac.jp https://orcid.org/0000-0001-9655-3985 Search for other works by this author on: Oxford Academic PubMed Google Scholar Atsuhito Takeda, Atsuhito Takeda Department of Pediatrics, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan https://orcid.org/0000-0001-9913-5834 Search for other works by this author on: Oxford Academic PubMed Google Scholar Kei Murayama Kei Murayama Center for Medical Genetics, Department of Metabolism, Chiba Children's Hospital, Chiba, JapanDiagnostics and Therapeutics of Intractable Diseases, Intractable Disease Research Center, Graduate School of Medicine, Juntendo University, Tokyo, Japan Search for other works by this author on: Oxford Academic PubMed Google Scholar European Heart Journal, ehae309, https://doi.org/10.1093/eurheartj/ehae309 Published: 24 May 2024

The retina is an intricately organized neural tissue built on cone and rod pathways for color and night vision. Genetic mutations that disrupt the proper function of the rod circuit contribute to blinding diseases including retinitis pigmentosa and congenital stationary night blindness (CSNB). Down Syndrome cell adhesion molecule like 1 (Dscaml1) is expressed by rods, rod bipolar cells (RBCs), and sub-populations of amacrine cells, and has been linked to a middle age onset of CSNB in humans. However, how Dscaml1 contributes to this visual deficit remains unexplored. Here, we probed Dscaml1's role in the maintenance of the rod-to-RBC synapse using a loss of function mouse model. We used immunohistochemistry to investigate the anatomical formation and maintenance of the rod-to-RBC synapse in the young, adult, and aging retina. We generated 3D reconstructions, using serial electron micrographs, of rod spherules and RBCs to measure the number of invaginating neurites, RBC dendritic tip number, and RBC mitochondrial morphology. We find that while rod-to-RBC synapses form and are maintained, similar to wildtype, that there is an increase in the number of invaginating neurites in rod spherules, a reduction in RBC dendritic tips, and reduced mitochondrial volume and complexity in the Dscaml1 mutant retina compared to controls. We also observed precocious sprouting of RBC dendrites into the outer nuclear layer (ONL) of the Dscaml1 mutant retina compared to controls. These results contribute to our knowledge of Dscaml1's role in rod circuit development and maintenance and give additional insight into possible genetic therapy targets for blinding diseases and disorders like CSNB.

The functional deterioration and loss of motor neurons are tightly associated with degenerative motor neuron diseases and aging-related muscle wasting. Motor neuron diseases or aging-related muscle wasting in turn contribute to increased risk of adverse health outcomes in the elderly. Cdon (cell adhesion molecule-downregulated oncogene) belongs to the immunoglobulin superfamily of cell adhesion molecule and plays essential roles in multiple signalling pathways, including sonic hedgehog (Shh), netrin, and cadherin-mediated signalling. Cdon as a Shh coreceptor plays a critical role in motor neuron specification during embryonic development. However, its role in adult motor neuron function is unknown. Hb9-Cre recombinase-driven motor neuron-specific Cdon deficient mice (mnKO) and a compound mutant mice (mnKO::SOD1G93A ) were generated to investigate the role of Cdon in motor neuron degeneration. Motor neuron regeneration was examined by using a sciatic nerve crush injury model. To investigate the phenotype, physical activity, compound muscle action potential, immunostaining, and transmission electron microscopy were carried out. In the mechanism study, RNA sequencing and RNA/protein analyses were employed. Mice lacking Cdon in motor neurons exhibited middle age onset lethality and aging-related decline in motor function. In the sciatic nerve crush injury model, mnKO mice exhibited an impairment in motor function recovery evident by prolonged compound muscle action potential duration (4.63±0.35 vs. 3.93±0.22s for f/f, P<0.01) and physical activity. Consistently, neuromuscular junctions of mnKO muscles were incompletely occupied (49.79±5.74 vs. 79.39±3.77% fully occupied neuromuscular junctions for f/f, P<0.0001), suggesting an impaired reinnervation. The transmission electron microscopy analysis revealed that mnKO sciatic nerves had smaller axon diameter (0.88±0.13 vs. 1.43±0.48μm for f/f, P<0.0001) and myelination defects. RNA sequencing of mnKO lumbar spinal cords showed alteration in genes related to neurogenesis, inflammation and cell death. Among the altered genes, ErbB4 and FgfR expressions were significantly altered in mnKO as well as in Cdon-depleted NSC34 motor neuron cells. Consistently, Cdon-depleted NSC34 cells exhibited elevated levels of cleaved Caspase3 and γH2AX proteins, as well as Bax transcription. Cdon-depleted NSC34 cells also exhibited impaired activation of Akt in response to neuregulin-1 (NRG1) treatment. Our current data demonstrate the functional importance of Cdon in motor neuron function and nerve repair. Cdon ablation causes alterations in neurotrophin signalling that leads to motor neuron degeneration.

Heyn-Sproul-Jackson syndrome (MIM#618724: HESJAS) is an autosomal dominant disorder that is characterized by growth retardation, microcephaly, developmental disabilities, and intellectual disabilities (DD/ID).1 HESJAS is caused by gain-of-function (GoF) variants of the DNMT3A, whereas Tatton-Brown-Rahman syndrome (MIM#615879: TBRS) caused by loss-of-function variants of the DNMT3A presents a counterpart phenotype characterized by overgrowth, distinctive facial dysmorphism and DD/ID (Table 1).2 So far, only four patients have been reported, and clinical information is limited to the childhood period.1, 3 Here, we report an adult patient of HESJAS. The patient was a 24-year-old female born at 41 weeks of gestation to non-consanguineous healthy Japanese parents. Her birth weight was 2492 g (−2.3SD) and head circumference was 32.5 cm (−0.9SD). The elder brother of the patient had DD/ID with unknown cause. The age of three, she was noted to have delayed developmental milestones. At 20 years of age, the visual acuity examination revealed no visual impairment, but in the following year prominent vision loss due to bilateral cataracts emerged and surgery was effective in improving her vision. At 24 years of age, she had a height of 138.2 cm (−4.0SD), body weight of 45.0 kg (−1.8SD), and head circumference of 49.3 cm (−4.8SD). The dysmorphic features included brachycephaly, sparse scalp hair, and brachydactyly (Supporting Information). Communication skills were limited to short sentences. Exome analysis of genomic DNA derived from the peripheral blood using trio samples showed a de novo heterozygous missense variant of the DNMT3A which categorized as pathogenic according to ACMG/AMP guideline: NM_022552.4 c.916 T > C p.(Trp306Arg). DNMT3A belongs to DNA methyltransferase family and promotes DNA methylation with recognition of histone H3 lysine-36 (H3K36) in the PWWP domain.4Phe303, Trp306, Trp330, Asp333 in the PWWP domain form the aromatic cage that recognize of H3K36.5 The previously reported variants in Trp330Arg and Asp333Asn were assumed to GoF through the functional analysis.1, 6 The variant of presently reported patient occurred at residue Trp306 of the aromatic cage and presumed to exert GoF of DNMT3A, but we could not perform functional analysis. It is difficult to confirm the external findings because there is no photograph of patients with HESJAS. Although there has been a report of HESJAS with craniosynostosis,3 there were no cranial CT findings suggestive of early fusion in the present patient. When combined with previously reported descriptions,1 DD/ID, microcephaly exceeding −4.0SD or skull deformation, and facial dysmorphism with sparse hair were considered common features of HESJAS (Table 1). Interestingly, the patient suffered vision loss proceeded at an unexpected rate in young adults. In the research using Drosophila with no endogenous methylation, it was reported that the expression of Dnmt3a of mouse induced into Drosophila resulted in microphthalmia or anophthalmia.7 The GoF variants in the DNMT3A may have caused ocular conditions associated with a present patient. DNMT3A is known to be associated with middle-aged onset hematopoietic disease, and TBRS may predispose to malignancies.2 To our knowledge, in causative genes for overgrowth syndrome, there have not been reported that another pathogenesis has a similar tumor risk. Tumor development has not been reported in HESJAS, tumor risk may be a future concern. In conclusion, HESJAS is included in the differential diagnosis of patients with DD/ID, marked microcephaly, and distinctive face. The preventive medical care for ophthalmologic complications was considered in long-term health management. We appreciate the patient's family members for permission to publish this report including clinical photographs. This work was supported by Research on Rare and Intractable Diseases from the Ministry of Health, Labour and Welfare, Japan, and Initiative on Rare and Undiagnosed diseases [Grant number JP22ek0109549] by the Japan Agency for Medical Research and Development. The authors declare no conflict of interest. Supporting Information: Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

With the increase in aging population in China, elderly Crohn's disease (CD) patients need to receive more attention. This study aims to explore the clinical characteristics and disease process of elderly onset CD (EOCD) patients in a single center. From January 2002 to January 2022, a total of 221 patients with CD from the Seventh Medical Center of Chinese PLA General Hospital were enrolled. According to the Montreal CD classification standard, the patients were further divided into 4 groups: an EOCD group (≥60 years old, n=25), a middle age onset CD (MOCD) group (40-59 years old, n=46), a young onset CD (YOCD) group (17-40 years old, n=131), and a childhood onset CD (COCD) group (6-16 years old, n=19). We compared the clinical characteristics and long-term prognosis among them. Females were predominant in the EOCD group (15/25, 60%). The number of people without smoking in the EOCD group (80%) was lower than that in COCD group (100%), higher than that in the YOCD group (70.2%) and the MOCD group (69.6%) (all P<0.05). Patients with perianal diseases at diagnosis were rare in the EOCD group (0%), lower than that in the COCD group (21.1%) and the YOVD group (19.8%) (all P<0.05). Stenosis was the most common disease behavior in the EOCD group (63.0%), significantly higher than that in the COCD group (15.8%), the YOCD group (36.6%) and the MOCD group (43.5%) (all P<0.05). The EOCD group was easier to be misdiagnosed as tumor (24%), higher than that in the COCD group (0%), the YOCD group (6.9%) and the MOCD group (19.6%) (all P<0.05). The EOCD group was prone to comorbidities (52%), and 20% of them were complicated with multiple comorbidities (P<0.05). During the follow-up, the all-cause mortality of EOCD was 12%, and the CD-related mortality was 8%, which was significantly higher than the other groups (all P<0.05). The use of immunosuppressants in the EOCD group (4.8%) was lower than that in the COCD group (12.8%), the YOCD group (16.8%) and the MOCD group (16.1%), but there was no statistical significance among the 4 groups (P=0.467). In addition, there was no significant difference in the rate of intestinal resection among the 4 groups (P=0.062). In EOCD patients, females were predominant, smoking was less common, and they were prone to comorbidity. At the initial stage of diagnosis, it is easy to be misdiagnosed as tumor, and the disease behavior mainly showed stricture type, less complicated with perianal diseases. During the follow-up, all-cause mortality and CD-related mortality of EOCD patients were significantly higher than those of the non-elderly onset CD patients.

BackgroundNeuromyelitis optica spectrum disorder (NMOSD) causes relapsing inflammatory attacks in the central nervous system, leading to disability. As rituximab, a B-lymphocyte-depleting monoclonal antibody, is an effective in preventing NMOSD relapses,...

Mahjong is one of the most popular Chinese tile games played in Japan. Mahjong-related seizures (MRS) are rare praxis-induced seizures. We identified three patients with MRS from February 2000 to February 2021. All cases were men, with a middle-age onset, generalized convulsive seizures, and lack of non-provoked, myoclonic, and absence seizures. All patients had no or non-specific neuroimaging or electroencephalogram abnormalities. They did not have features linked to idiopathic generalized epilepsy. All patients were seizure-free after behavioral adjustments, although one patient required anti-seizure medication and avoided long duration games. These changes may help other patients with MRS continue playing Mahjong.

The pathogenicity of the different genetic variants causing hypertrophic cardiomyopathy (HCM) and the genotype/phenotype correlations are difficult to assess in clinical practice, as most mutations are unique or identified in non-informative families. Pathogenic variants in the sarcomeric gene MYBPC3 inherited with an autosomal dominant pattern, whereas incomplete and age-dependent penetrance are the most common causes of HCM. We describe the clinical characteristics of a new truncating MYBPC3 variant, p.Val931Glyfs*120, in 75 subjects from 18 different families from northern Spain with the p.Val931Glyfs*120 variant. Our cohort allows us to estimate the penetrance and prognosis of this variant. The penetrance of the disease increases with age, whereas 50% of males in our sample developed HCM by the age of 36 years old, and 50% of women developed the disease by the time they reached 48 years of age (p = 0.104). Men have more documented arrhythmias with potential risk of sudden death (p = 0.018), requiring implantation of cardioverter defibrillators (p = 0.024). Semi-professional/competitive sport among males is related to earlier onset of HCM (p = 0.004). The p.Val931Glyfs*120 truncating variant in MYBPC3 is associated with a moderate phenotype of HCM, with a high penetrance, onset in middle age, and a worse outcome in males due to higher risk of sudden death due to arrhythmias.

Objective: To explore the associations between arterial stiffness (AS) onset age and type 2 diabetes (T2DM) risk. Design and Method: This study enrolled 22,588 participants free of T2DM at baseline. All participants take an annual physical examination from 2012 to 2016, with fasting blood glucose and brachial-ankle pulse wave velocity measurements. Cox proportional model was used to investigate the association between AS onset age and T2DM risk. Sex specific analysis was also performed, as well as examining the association between early vascular aging (EVA), normal vascular aging (NVA), supernormal vascular aging (SUPERNOVA) onset age, and diabetes risk. Results: Totalling 757 (3.4%) participants were diagnosed with T2DM. Compared with participants free of AS in each specific age group, the earlier AS onset age was more strongly associated with T2DM risk, especially for the middle age, with the fully adjusted hazard risk (HR) and 95% confidence interval (CI) of 4.63 (2.79, 7.67) for AS onset age at 50. Similar results were observed both in males and females, with the fully adjusted HR and 95% CI of 4.54 (2.60, 7.93) for males and 4.86 (1.48, 16.01) for females, with AS onset age at 50. Such association was also observed in the exploration of EVA, NVA, and SUPERNOVA onset age and incident T2DM risk. Conclusions: This study revealed that middle-aged onset of AS was more significantly associated with a higher risk of T2DM. Early screening of AS, especially in middle age, may assist in T2DM detection and postpone diabetic vascular complications developing.

Background: There are two approaches to the determination of the population at risk of atherothrombotic disease: the herd approach and the targeted approach. In the former scenario, all people are treated, usually with lifestyle changes, but also with medications at times. In the latter scenario, only those deemed at risk of atherothrombotic disease are treated. The author has always favored the latter approach, but for the target approach to be effective, one must know the population at low risk of atherthrombotic disease. Objectives: The purpose of this manuscript is to demonstrate that the population at low risk of atherothrombotic disease can be readily identified and needless treatment can be avoided. Methods: The author has conducted a chart review of his family practice patients roster and separated out the cohort of those who developed some form of atherothrombtic disease from the general population cohort. Results: The author has shown that three major risk factors for atherothrombotic disease can accurately define the population at low risk of atherothrombotic disease: no use of cigarettes, lack of dyslipidemia, and lack of hypertension. Dyslipidemia is defined in terms of the Cholesterol retention Fraction, defined as the difference between low-density lipoprotein cholesterol and high-density lipoprotein cholesterol, that difference divided by the low-density lipoprotein cholesterol, but also whenever low-density lipoprotein cholesterol exceeds 170mg/dl. Hypertension is defined as a systolic blood pressure of 140mmHG or higher or any blood pressure that is being treated. Additionally, the author has shown that in the absence of these three major risk factors, the presence of diabetes mellitus is not associated with early onset atherothrombotic disease. Conclusions: People who do not manifest the three major risk factors for atherothrombotic disease (cigarette smoking, dyslipidemia, and hypertension)are not at risk of early or middle-age onset atherothrombotic disease. Such people do not require therapy though the high blood sugar levels of uncontrolled diabetes mellitus will require treatment to prevent microvascular disease.

BackgroundHuman induced pluripotent stem cell (iPSC)-derived cardiomyocytes (iPSC-CMs) do not display all hallmarks of mature primary cardiomyocytes, especially the ability to use fatty acids (FA) as an energy source, containing high mitochondrial mass, presenting binucleation and increased DNA content per nuclei (polyploidism), and synchronized electrical conduction. This immaturity represents a bottleneck to their application in (1) disease modelling—as most cardiac (genetic) diseases have a middle-age onset—and (2) clinically relevant models, where integration and functional coupling are key. So far, several methods have been reported to enhance iPSC-CM maturation; however, these protocols are laborious, costly, and not easily scalable. Therefore, we developed a simple, low-cost, and rapid protocol to promote cardiomyocyte maturation using two small molecule activators of the peroxisome proliferator-activated receptor β/δ and gamma coactivator 1-alpha (PPAR/PGC-1α) pathway: asiatic acid (AA) and GW501516 (GW).Methods and ResultsMonolayers of iPSC-CMs were incubated with AA or GW every other day for ten days resulting in increased expression of FA metabolism-related genes and markers for mitochondrial activity. AA-treated iPSC-CMs responsiveness to the mitochondrial respiratory chain inhibitors increased and exhibited higher flexibility in substrate utilization. Additionally, structural maturity improved after treatment as demonstrated by an increase in mRNA expression of sarcomeric-related genes and higher nuclear polyploidy in AA-treated samples. Furthermore, treatment led to increased ion channel gene expression and protein levels.ConclusionsCollectively, we developed a fast, easy, and economical method to induce iPSC-CMs maturation via PPAR/PGC-1α activation. Treatment with AA or GW led to increased metabolic, structural, functional, and electrophysiological maturation, evaluated using a multiparametric quality assessment.

Cerebellar ataxia with neuropathy and vestibular areflexia syndrome (CANVAS) refers to a multi-system neurodegenerative disorder, with middle-age onset, which mainly presents with progressive imbalance. Imbalance is attributable to isolated or combined impairment of the cerebellar, proprioceptive, and vestibular systems. Chronic spasmodic cough, which usually precedes neurological symptoms, serves as a useful diagnostic clue to CANVAS. Diagnostic criteria have been proposed for CANVAS in 2016, based on 3 cardinal features. In 2019, a biallelic intronic AAGGG repeat expansion (AAGGG)exp in the replication factor complex subunit 1 gene (RFC1) was identified as a genetic contributor to CANVAS, and (ACGGG)exp in RFC1 was subsequently confirmed as a causative factor for CANVAS. Genetic screening for RFC1 has shown that CANVAS is an overlooked entity in patients with cerebellar ataxia or sensory neuropathy, which highlights more restricted phenotypes that exclusively involve one of the aforementioned systems. The phenotypic spectrum of RFC1-related disorders has been expanding since the discovery of (AAGGG)exp or (ACGGG)exp in the RFC1. Studies have reported atypical features, including parkinsonism, motor neuron involvement, cognitive decline, and sleep disorders. Currently, a wide variety of clinical conditions associated with biallelic intronic pentanucleotide repeat expansion in RFC1 are classified as RFC1 CANVAS/spectrum disorder.